Conclusions

Discovery of the mutations underlying ADCA and the correlations between CAG repeat length and clinical or neuropathological features of genetically specific sub-forms of these diseases have simplified the molecular diagnosis and permit analysis of patients classified according to their genotype, a necessary step in the development of a precise nosology and a better follow up of the patients. Although it is often impossible to anticipate the SCA mutation on the basis of clinical criteria since phenotype depends on the locus, the size of the repeat expansion, the duration of the disease and other unknown factors, analysis of the molecular and clinical characteristics have revealed group differences that will be helpful for understanding the history and disease course of patients with ADCA.

The cause of the molecular instability and the pathophysiological consequences of the expanded polyQ tract remain partially unknown, and therapeutic intervention will require elucidation of the underlying pathogenic mechanism. Animal and cellular models are helping us to understand the processing of the pathological proteins and identify their molecular partners. New research areas are emerging and others are being refocused: level of protein expression,198 dysfunction of the transcription machinery and mosaicism of the repeat in the CNS.51 The identification of modifiers of disease severity, involved in RNA processing, transcriptional regulation and cellular detoxification, in an SCA1 Drosophila model is providing important clues to the pathological process and to the great variability in disease expression.198

Diagnosis Considerations

Identification of ADCA genes and their mutations enables routine diagnostic testing of individuals who already present with symptoms of the disease. Molecular analysis is also useful to distinguish disorders which are clinically similar or which may be confused with other diseases because of their extremely variable clinical presentation. DNA testing in asymptomatic at-risk individuals, however, raises many difficult ethical issues for severe adult-onset disorders for which no treatment can be proposed and for which age at onset cannot be precisely predicted from the number of CAG repeats. The international guidelines for Huntington's disease should also be followed for ADCA.199

Molecular diagnosis of isolated cases is also crucial. Positive isolated cases rarely carry de novo mutation.68,200 More frequently, they reflect missing family histories if the transmitting parent died before onset of symptoms or is still asymptomatic because of marked anticipation.63,84 In our experience, the yield of positive molecular testing in the absence of family history does not exceed 3%.

Case of SCA6

Although the mutational mechanism in SCA6 is a translated, but small, CAG expansion, it is not clear whether the pathogenic mechanism is similar to the other dominant spinocerebellar ataxias caused by the same kind of mutation. An alteration of the calcium homeostasis has been implicated by several, albeit controversial, stud-ies.201-203

Detoxify the Body

Detoxify the Body

Need to Detoxify? Discover The Secrets to Detox Your Body The Quick & Easy Way at Home! Too much partying got you feeling bad about yourself? Or perhaps you want to lose weight and have tried everything under the sun?

Get My Free Ebook


Post a comment